Computational prediction of adenosine receptor homodimerization

COMP 241

Soo-Kyung Kim,, Materials and Process Simulation Center, California Institute of Technology, 1200 East California Blvd., Beckman Institute (Mail Stop: 139-74) Rm. 054a, Pasadena, CA 91125 and Kenneth A. Jacobson,, Molecular Recognition Section, NIDDK, NIH, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892-0810.
Increasing evidence suggests that G protein-coupled receptors (GPCRs) form functional dimers or larger oligomeric complexes through homodimerization or heterodimerization. In this study, symmetrical homodimers of the A3 adenosine receptor (AR) with various transmembrane (TM) contact sites, TM1-2, TM2-3, TM2-4, TM3-4, TM4-5, TM5-6, TM6-7, and TM7-1, were generated by a “fit-atoms” method using eight centroids of the TM centroids, and normal atom passed through the plane containing all centroids. Following molecular dynamics, several contact sites, TM1-2, TM2-4, and TM4-5, were energetically stable. Through the calculation of the area of the contact sites in various dimers using MOLCAD surface program, the TM4-5 dimer had the most TM contact area among homodimers, consistent with the atomic force microscopy result of bovine rhodopsin in native membrane, in which TM4-5 was the contact site. In addition, the TM4-5 dimer made by this theoretical method was more stable than the TM4-5 dimer generated by the semi-empirical method.